Aging is often associated with an imbalance between food intake and metabolism, reflected in increased body weight and fat at middle age and reduced food intake at old age. Weight gain, particularly as abdominal fat, is a major risk factor for type II diabetes, heart disease, and stroke, which can significantly reduce lifespan and quality of life. Inadequate food intake late in life can also impair maintenance of lean body mass and immunity. Disruption of hypothalamic melanocortin pathways has been implicated in appetite dysregulation, as well as hyperinsulinemia, leptin resistance, and weight gain, all of which have been reported in aging. Hypothalamic pro-opiomelanocortin (POMC), a major source of melanocortin receptor ligands proposed to inhibit appetite, has been shown to decrease during aging in experimental animals. Glucocorticoids have been found to increase with aging, and to promote food intake, insulin resistance and fat deposition in a leptin-independent manner. We hypothesize that decreased hypothalamic POMC expression and increased glucocorticoid production contribute to leptin resistance, representing reduced sensitivity to signals of nutritional repletion. This leptin resistance results in weight gain at middle age, while age-related loss of brain corticosteroid receptors and compensation for inadequate POMC expression may account for anorexia in old age. To test this hypothesis, we will compare leptin and corticosteroid regulation of food intake, body composition, plasma hormones, and gene expression of corticosteroid receptors, POMC and related melanocortin ligands and receptors, in young and aging mice. These studies will identify neuropharmacological mechanisms for regulating food intake and metabolism that will aid in optimizing appetite and body weight control for healthy aging.